Tilburg University
Interventions for cognitive deficits in patients with a brain tumor
Gehring, K.; Aaronson, N.K.; Taphoorn, M.J.B.; Sitskoorn, M.M.
Published in:Expert Review of Anticancer Therapy DOI:
10.1586/ERA.10.163
Publication date: 2010
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Publisher's PDF, also known as Version of record
Link to publication in Tilburg University Research Portal
Citation for published version (APA):
Gehring, K., Aaronson, N. K., Taphoorn, M. J. B., & Sitskoorn, M. M. (2010). Interventions for cognitive deficits in patients with a brain tumor: An update. Expert Review of Anticancer Therapy, 10(11), 1779-1795.
https://doi.org/10.1586/ERA.10.163
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Karin Gehring†1, Neil K Aaronson2, Martin J Taphoorn3,4 and Margriet M Sitskoorn1
1Center of Research on Psychology in
Somatic Diseases (CoRPS), Tilburg University, Room P 512, PO Box 90153, 5000 LE Tilburg, The Netherlands
2Division of Psychosocial Research and
Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121,
1066 CX Amsterdam, The Netherlands
3Medical Centre Haaglanden,
Department of Neurology, PO Box 432, 2501 CK The Hague, The Netherlands
4Department of Neurology,
VU University Medical Center, Amsterdam, The Netherlands
†Author for correspondence:
Tel.: +31 134 663 738 Fax: +31 134 662 067 k.gehring@uvt.nl
Patients with brain tumors may suffer from cognitive deficits caused by the disease and/or its treatment. Here, we review recent efforts in the research on prevention or treatment of cognitive deficits in these patients. We conclude that interest in this area is growing, but that methodological difficulties persist. In addition, we describe the recently completed first randomized controlled trial on the effectiveness of cognitive rehabilitation that we conducted in patients with brain cancer. By reflecting on the methodological challenges experienced in our trial, we hope to assist others in planning and conducting future studies on both pharmacological treatments and cognitive rehabilitation programs for cognitive deficits in this patient population. We conclude with suggestions for future research directions.
Keywords: brain tumor • cognitive deficits • cognitive rehabilitation • intervention • neuropsychological impairment
Interventions for cognitive
deficits in patients with a brain
tumor: an update
Expert Rev. Anticancer Ther. 10(11), 1779–1795 (2010)
effects [11,14,15]. As compared with other causes,
the pathogenesis of the cognitive side effects due to late radiation damage is relatively well known. Demyelination and microvascular injury, leading to necrosis [16,17], inflammation
and impaired hippocampal neurogenesis, have been implicated in radiation-induced cogni-tive impairment [18–20]. Although the cognitive
effects of chemo therapy are less clear, they might result from comparable mechanisms [21,22].
Antiepileptic drugs also have adverse effects
[11,14,15,20,23]. Other medical factors and
com-plications, including endocrine and metabolic disturbances, infection and anemia, can also contribute to the cognitive deficits [24–26].
Genetic risk factors are increasingly associated with individual neurotoxic reactions to invasive treatments such as chemotherapy [20]. Finally,
psychological reactions to the disease such as anxiety and depression may also have cognitive effects [11,27]. A combination of these factors
most probably explains the cognitive impairment observed in patients with brain tumors.
The cognitive deficits experienced by most patients with a brain tumor appear to be milder and more diffuse than would be predicted by site alone [28,29]. Nevertheless, these deficits can
substantially impact on patients’ lives [30], and
are particularly an issue in those patients with a more favorable prognosis, such as patients Patients with primary brain tumors and those
with brain metastases may suffer from cognitive deficits caused by the disease and/or its treatment. Deficits are often observed in the broad domains of attention, memory, executive functioning and language [1–3].
There is a good deal of variability across stud-ies in the reported prevalence of cognitive defi-cits in these patient populations. The rates range from 29% in nonirradiated low-grade glioma patients [1] to approximately 90% in diverse
brain tumor groups [1,4–6]. This variability may
be due to differences in the specific populations of patients studied, tumor treatment variables, neuropsychological tests used, and cut-off scores and normative data used to establish ‘caseness’. Nevertheless, it is clear that patients with a brain tumor have cognitive deficits that are more prominent than in patients with extracranial malignancies with a similar prognosis [4,7].
Although the exact pathophysiology of the observed cognitive impairments is not entirely understood, several causes can be discerned, including the tumor (location, size, progression and growth rate), tumor-related neurological complications and epilepsy [8–13]. Cancer
with a lower grade glioma. After tumor treatment, many of these patients may live free from (severe) neurological symptoms for years until the disease progresses. During this period, as these patients attempt to resume family, work and social activities, they may begin to experience cognitive deficits. Cognitive symptoms are reported in as many as 80% of patients with a brain tumor, placing them among the most commonly reported neurological problems in this population of patients [25,31].
In the broad field of brain disorders and diseases, advances in treatment and the resulting improvement in survival rates has led to increased interest in developing effective physical, mental and cognitive rehabilitation programs. Two approaches are often undertaken in the treatment of cognitive deficits: pharmacologi-cal and neuropsychologipharmacologi-cal (i.e., cognitive rehabilitation). While pharmacological treatment of cognitive deficits may be familiar to most readers, this may be less so for ‘cognitive rehabilitation’. In short, cognitive rehabilitation refers to nonpharmacological interventions aimed at preventing or treating cognitive deficits. While not exhaustive, for illustrative purposes we will briefly describe five common types of cognitive interventions. First, the environment can be modified or restructured to help patients meet the demands of independent daily living by relying less upon their impaired cognitive abilities [32]. The nature or degree
of such modifications will vary depending on the severity of the cognitive problems. Second, patients can be taught to make use of external aids and technology, such as electronic diaries. Third, via structured strategy training, patients can be taught to apply internal strategies to cope with their cognitive prob-lems. This includes pacing of cognitive activities, preventing or minimizing distractions, anticipating and planning, or the use of mnemonics. Fourth, rehabilitation can focus on retraining specific cognitive skills by means of frequently practiced exercises (‘repetitive stimulation’). Such retraining can, for example, focus on attention, memory or executive functioning. Finally, psycho-education with regard to brain functioning, cognitive deficits and their consequences for daily life may be of value to patients and their families.
Studies among patient populations with other types of acquired brain injury, such as stroke and traumatic brain injury, have dem-onstrated the effectiveness of cognitive rehabilitation [33–39], with
most programs combining strategy training and/or retraining with psychoeducation.
Specific to brain tumors, our previous review identified sur-prisingly few studies on pharmacological or neuropsychological interventions for cognitive deficits [40]. The few (predominantly
Phase II) studies of pharmacological interventions and cognitive rehabilitation programs reported some degree of success. However, the results were often difficult to interpret owing to methodologi-cal limitations, some of which are common to Phase II trials, including nonrandomized study designs, failure to include a con-trol group to rule out practice and other effects, small sample sizes, and absence of formal statistical testing. As a result, convincing evidence for a positive effect of pharmacological agents or cogni-tive rehabilitation on neuropsychological functioning could not be found.
Reasons for the paucity of cognitive intervention studies in this population compared with other types of acquired brain injury may include the relatively low incidence of brain tumors, their progressive nature and the relatively poor prognosis associated with the disease. Historically, research in brain cancer has been primarily focused on identifying treatments that are effective in terms of tumor control and survival. Gradually, as the rates of disease-free survival have increased, interest has expanded to include concern with long-term sequelae of the disease and its treatment, including cognitive impairment. At the same time, evidence for the efficacy of treatments for cognitive deficits in other patient populations has accumulated (e.g., see [33,41,42]),
leading to a greater acceptance of cognitive rehabilitation as a legitimate goal in the treatment of brain cancer.
The mild-to-moderate global cognitive deficits seen in patients with brain cancer may be most amenable to cognitive treatment. Particularly in the case of low-grade gliomas, where the tumor grows slowly and infiltrates or displaces neuronal tissue with-out actually destroying it [8,28], some residual function may be
maintained and/or reshaping or local reorganization of functional networks may take place [11,43,44].
In fact, studies of functional outcome after inpatient reha-bilitation have indicated similar, or even better, outcomes for patients with a brain tumor than for individuals with trau-matic brain injury or stroke, matched on demographic, medi-cal and/or functional characteristics [45–47]. This suggests that
patients with a brain tumor may also be good candidates for cognitive intervention.
In our previous review, we mentioned a number of forthcom-ing or ongoforthcom-ing studies (identified via Clinicaltrials.gov [201]) that
were, at that time, not sufficiently mature to report results. In the current paper, we will review these studies and other recent phar-macological and cognitive rehabilitation approaches in patients with brain cancer. We will also summarize the results of a large randomized controlled trial (RCT) that we recently completed on the effectiveness of a cognitive rehabilitation program for patients with brain tumors [48], focusing in particular on some
of the methodological issues arising from that study. Hopefully, the reflections on our experience in conducting such research will assist others in planning and conducting future studies in this area. Finally, we will provide some suggestions for future research directions.
Current state of research on interventions for cognitive deficits in patients with a brain tumor
We will first discuss the results of the most recent studies of the prevention of cognitive deficits in patients with a brain tumor. This will be followed by an update on pharmacologi-cal and neuropsychologipharmacologi-cal interventions for the treatment of cognitive deficits.
Novel studies of targeted brain tumor treatments
Radiation Therapy Oncology Group (RTOG) 0933 is a planned Phase II clinical trial of avoidance of the hippocampus plus a 5 mm margin during whole-brain radiotherapy (WBRT) to prevent radiation-induced cognitive decline in patients with brain metastases, without compromising intracranial disease con-trol. In preparation for this trial, Gondi and colleagues sought to estimate the risk of disease progression within the hippocampal avoidance region to determine the safety profile of the interven-tion [49]. Axial images from pretreatment, postcontrast MRIs were
retrospectively used to contour each metastasis and hippocampus in 371 patients. A total of 1133 brain metastases were identified. Metastases within 5 mm of the hippocampus were observed in 8.6% of the patients. Based on this perihippocampal meta stasis risk of only 8.6%, the authors concluded that hippocampal avoidance during WBRT is safe for clinical testing. The trial on the cognitive effects of this more targeted tumor treatment is scheduled to open in 2010.
Another study of a comparable treatment was terminated “due to new research priorities” [202]. As discussed in our previous
review, this planned Phase III randomized open-label study in 30 patients with one to six metastases was initiated to investigate whether neural stem cell-preserving WBRT would result in an improved cognitive profile over standard WBRT by minimizing radiation to brain areas where neural stem cells are located, such as the hippocampal area.
Correa and colleagues investigated a modified treatment regi-men consisting of methotrexate-based chemotherapy incorporat-ing rituximab, a chimeric monoclonal antibody, and reduced-dose WBRT aimed at improving efficacy and decreasing neurotoxicity in primary CNS lymphoma patients in a prospective, uncon-trolled study [50]. Of the 19 patients with primary CNS
lym-phoma, 12 completed neuropsychological assessments at diag-nosis, after induction chemotherapy and prior to reduced-dose WBRT and consolidation chemotherapy, and approximately 6 and 12 months after treatment. Seven patients dropped out for various reasons. Nine of the 12 patients completed additional cognitive evaluations (including tests of verbal memory, atten-tion/executive functioning and motor speed) approximately 18 and 24 months post-treatment. Following treatment, cognitive functioning improved significantly, possibly owing to tumor treatment, discontinuation of some drugs, regression to the mean and/or practice effects. Up to 2-year follow-up, there was an absence of the significant decline of cognitive functioning that is frequently reported in studies of conventional combined-modality therapy. However, some difficulties in verbal memory and motor speed already observed at baseline persisted over the follow-up period. Furthermore, there was a mild increase in treat-ment-related white matter disease until 12 months post-treatment that did not increase further thereafter.
An uncontrolled Phase II study of the possible preservation of cognitive function by surgical intervention and insertion of gliadel wafers (wafers that slowly release the chemotherapy agent carmustine) [203] without postoperative WBRT aims to recruit
75 patients with brain metastases. Data collection is expected to be completed in March 2011.
Studies of pharmacological prevention in patients with brain tumors
Research on pharmacological neuroprotective agents to protect healthy tissue against treatment-induced neuronal cell loss or degen-eration is still in a predominantly preclinical phase (Table 2). The one study in humans was terminated early owing to slow accrual and high drop-out rates [51]. The data from planned or ongoing studies
of neuroprotective agents in humans cited in our previous review are not yet available. The Phase I study on the efficacy of lithium in protecting normal cells from side effects of WBRT was completed in March 2009, having recruited 24 patients with multiple brain metastases [204]. The results have not yet been published.
The large-scale, randomized, double-blind, placebo-controlled study by Brown and colleagues on the efficacy of memantine, a NMDA receptor antagonist that is also used in Alzheimer’s dis-ease, in preventing cognitive deficits in patients with brain metas-tasis during and after WBRT, aims to recruit 536 patients [205].
This trial is anticipated to be completed in June 2012.
Studies of pharmacological treatment in patients with brain tumors
In our previous review, it was not possible to draw any defini-tive conclusions about the efficacy of pharmacologic agents (e.g., methylphenidate) in the treatment of existing cognitive deficits in patients with brain tumors. In part, this was due to the methodological limitations of the studies reviewed.
Two of the trials mentioned in our earlier review have sub-sequently published their results. A trial on immediate-release methyl phenidate, sustained-release methylphenidate and modafinil in patients with a primary brain tumor was closed early owing to poor accrual (Table 3)[206]. It was hypothesized that patients receiving methylphenidate would improve on memory, executive function and psychomotor processing speed measures, while patients receiving modafinil would improve on attention measures. Data from 24 patients enrolled in this trial suggested that methylphenidate improved psychomotor processing speed but did not result in differential change in memory or execu-tive function measures [52]. The positive effects of modafinil on
measures of attention could not be demonstrated.
The second trial, an uncontrolled investigation of liothyronine added to levothyroxine in improving cognitive deficits resulting from damage to the hypothalamic–pituitary axis due to the brain tumor and its treatment with external-beam irradiation was also terminated owing to slow accrual [207]. In the ten patients who
were recruited into this study, liothyronine improved psycho-motor processing speed, but not memory [53]. A trend toward
improvement in executive function was also observed.
Two other pharmacological studies that we located on Clinicaltrials.gov have presumably been completed, but the results have not (yet) been published. The first is on hyperbaric oxygen therapy in patients with brain tumors and radiation necrosis (esti-mated study completion date: June 2005) [208]. The second is on
Several of the other clinical trials that we noted in our previ-ous review are still ongoing. A double-blind, placebo-controlled randomized trial is being conducted to investigate the efficacy of donepezil, an acetyl cholinesterase inhibitor in improving a neurocognitive symptom cluster (i.e., cognitive impairment, sub-jective confusion and fatigue) that has yielded positive results in Alzheimer’s disease and vascular dementia [210]. Data
collec-tion on 200 irradiated patients with primary or metastatic brain tumors was scheduled to be completed by June 2010. Another uncontrolled study of the effects of donepezil for improvement of executive abilities and psychomotor speed in patients with brain tumors who have cognitive deficits (n = 30) is also expected to be completed this year [211].
A randomized, placebo-controlled, double-blind trial on the fea-sibility of the stimulant armodafinil in relieving radiation-induced fatigue was initiated in March 2010 [212]. In total, 54 patients
with primary brain tumors will receive armodafinil or placebo beginning no later than the fifth fraction of brain radiotherapy and continuing for 9–11 weeks. In addition to fatigue, assessments will also include quality of life (QoL), and cognitive functioning at baseline and periodically during the study. Presence of cognitive deficits is not an inclusion criterion. Data collection is estimated to be completed in May 2011. Although the authors do not explicitly state that this is a prevention study, the timing of the armodafinil during radiotherapy suggests that the intervention is aimed at preventing fatigue and, possibly, cognitive deficits.
Studies of cognitive interventions in patients with brain tumors
In our former review, only one study of a cognitive/vocational approach in brain tumor patients could be identified [54]. The
(suggested positive) results of the study could not be fully inter-preted owing to the absence of a control group and the failure to use formal statistical testing.
Duval and colleagues reported a case study in which a com-prehensive program for the rehabilitation of working memory was employed in a young man who had undergone resection of a grade 2 ganglioglioma in the left temporal lobe (Table 4)[55]. The program consisted of two information sessions, 19 cognitive pro-gram sessions and seven ecological propro-gram sessions in 6 months. In total, 15 sessions of various neuropsychological evaluations and tests were held, including four sessions at a 3-month follow-up. Working memory deficits improved during and after the pro-gram. Subprocesses of working memory improved specifically after the corresponding rehabilitation components were com-pleted. Subjective cognitive functioning also improved and there was a carry-over effect to, what the authors called, “tasks with an ecological dimension”. The effects on neuropsychological test performance and subjective cognitive functioning were sustained until the 3-month follow-up.
Locke and colleagues conducted a pilot study of the feasibility and tolerability of a 2-week combined cognitive rehabilitation (particularly aimed at memory) and problem-solving inter vention for pairs of patients with (predominantly newly diagnosed) pri-mary brain tumors and their caregivers [56]. Patients were only
included if they had mild-to-moderate cognitive impairment. A total of 19 patient–caregiver dyads were enrolled, of which 16 were randomized to receive the intervention or standard medical care, and three were assigned directly to the intervention group. The intervention consisted of six sessions of cognitive rehabilitation and six sessions of problem-solving therapy that were provided concurrently with radiation therapy over the course of 2 weeks. Both study groups were reassessed immediately after the interven-tion and at 3-month follow-up, with primary outcome measures of QoL and functional capacity, and secondary outcome measures of cognitive functioning, caregiver burden, mood, fatigue, inter-vention feedback and the use of compensation techniques. The intervention group also completed a questionnaire for feedback on the intervention.
Although the authors concluded that patient participation was feasible, accrual was low (19 out of 160 patients). One of the main reasons for this was a low prevalence of cognitive defi-cits (38%) in patients. The authors suggested that the patients, who were newly diagnosed were too early in their disease and treatment course to expect measurable impairment. Other major reasons for the low accrual were patient decline of referral to the clinical neuropsychologist (16%) and a competing QoL research protocol in the cancer center (10%). A total of 13 patients com-pleted the entire study through the 3-month follow-up. Four out of 12 patients who were enrolled in the intervention group did not complete the intervention for various reasons. Seven of the eight dyads who completed the program found the intervention to be helpful. There was no significant intervention effect on the primary outcome measures of QoL and functional capacity, and too few patients completed the neuropsychological follow-up to allow for any statistical ana lysis of the neuropsychological test data.
In another pilot study, Hassler and colleagues evaluated the fea-sibility of group training sessions of Stengel’s holistic mnemonic training in patients with high-grade gliomas who were treated with maximal tumor resection, radiation and chemotherapy [57].
Six patients with glioblastoma multiforme and five with WHO grade III gliomas and good performance underwent the inter-vention consisting of ten 90-min sessions over 12 weeks. It was not required that participants had cognitive deficits. There was no control group. Neuropsychological assessments were performed pre- and postintervention. On four out of five test variables of various cognitive domains, patients showed variability in their performance, with worsening, improvement and stabilization of test scores. A significant group improvement in a verbal learning test variable was observed. The authors stated that all patients showed some improvement (although ‘improvement’ was not defined) in at least one of the four tests “and not the lack of improvement in repetitive testing which is frequently seen in patients with cognitive sequelae after systemic cancer therapy”. However, closer inspection of the studies they refer to shows that some included only one assessment (in which it is not possible to measure effects due to repetitive testing) and others used intervals between assessments of longer than 3 months, in which practice effects may be smaller.
Brigidi and colleagues are currently recruiting 20 dyads of patients with a high-grade (III or IV) glioma and a life expectancy of at least 6 months and their caregivers to a trial in which they will be randomized to coping-skills training, includ-ing problem solvinclud-ing, communication skills and managing activities, or a usual care control group
[213]. Evidence of problems in depression, fatigue,
sleep disturbance and/or cognitive impairment as indicated by the treating neuro-oncologist is one of the inclusion criteria. The study is expected to be completed by December 2011.
RCT on cognitive rehabilitation in patients with low-grade & anaplastic gliomas
We recently reported on the first RCT that evaluated the effects of a multifaceted cognitive rehabilitation program on cognitive functioning and selected QoL domains in 140 adult patients with low-grade and anaplastic gliomas, favorable prognostic factors, and both subjective cognitive symptoms and objective cognitive deficits [48,214]. Patients were randomized
to an intervention group or a waiting list control group. Most patients had undergone either biopsy (29%) or resection (66%), 61% had undergone radiotherapy, and 11% had had chemotherapy. The cognitive rehabilitation program that we developed consisted of six-weekly, 2-h individual sessions plus homework, and incorporated both computer-based attention retraining (C-Car) and psychoeduca-tion on and compensatory skills training of atten-tion, memory and executive functioning (strategy training; see [Gehring K, Aaronson NK, Taphoorn MJB, Sitskoorn MM. A cognitive rehabilitation program for patients with mild to moderate cognitive deficits evalu-ated in patients with brain tumors. Manuscript Submitted]
for more details on the program). The mean total time devoted to the entire cognitive rehabilitation program was 35 h over a period of 6 weeks; almost 6 h for the C-Car component and up to 30 h for the strategy component.
Participants completed a battery of neuropsycho-logical tests and self-report questionnaires on cog-nitive functioning, fatigue, mental health-related QoL and community integration at baseline fol-lowing completion of the program and at 6-months follow-up. For the primary statistical ana lysis of the result at the group level, a hierarchical approach of doubly multivariate repeated-measure analysis of covariance was used.
Although the intervention group reported a sig-nificant improvement in subjective cognitive func-tioning early on, and this was largely maintained through to the 6-month follow-up, the control group exhibited a smaller, more gradual improvement in
self-reported cognitive functioning over time. This improve-ment might reflect a combination of regression to the mean [58],
response shift [59] and natural recovery (e.g., see [60,61]). As a result,
differences in subjective cognitive functioning between the two groups diminished over time.
With regard to the objective neuropsychological test scores, no significant group differences were observed at immediate post-intervention. Closer inspection of the test scores suggested that improvement due to practice effects or regression to the mean in both groups may have initially overwhelmed any intervention effect in the experimental group. At the 6-month assessment, the intervention group exhibited continued improvement in objec-tive cogniobjec-tive performance on six neuro psychological measures of attention and verbal memory, while the control group did not. Significant intervention effects were also found for longer term mental fatigue scores.
In summary, the results of this RCT at the group level indicated a positive effect on short-term cognitive complaints, and longer term cognitive performance and mental fatigue level. The large majority of the participants indicated that they found most of the program elements to be very useful [Gehring K et al. Manuscript Submitted]. A substantial percentage (36%) of the participants
indicated that the strategy training involved a great deal of home-work, although only a few indicated that it was too burdensome. Older patients had more difficulty with the amount of homework involved than younger participants.
Expert commentary
Many of the published studies and those currently being carried out on the prevention or treatment of cognitive deficits in patients with brain tumors have methodological limitations that impact on both the quality of the research and the ability to draw firm conclusions. In our own research, we were also confronted with a number of methodological challenges and problems. In this section, we will address the most important of these method-ological issues, with an eye toward informing future research on both pharmacological and neuropsychological approaches to the cognitive rehabilitation of this patient population.
Among the methodological limitations, perhaps the most important is the failure to employ an appropriate control group in order to rule out practice effects (i.e., improved neuropsychologi-cal test performance due to repeated testing over time), and other effects such as regression to the mean or spontaneous recovery. Although it appears that more recent studies have employed a randomized controlled design more frequently, based on our own experiences, we would again like to emphasize the importance of the control group. In our RCT, we observed an initial improve-ment in test performance in the intervention group. Without the inclusion of a control group, we would have attributed this positive effect to the cognitive rehabilitation program. However, the fact that there was a similar improvement in the control group sug-gested a practice effect. The inclusion of a control group proved to be essential. Bruera and colleages had a comparable experience when testing methylphenidate for cancer fatigue [62,63]; although
in their initial pilot study the scores on a fatigue scale improved
significantly (by 17 points), the overall effects were markedly lower in their RCT (7.5 points for placebo and 9.6 points for methylphe-nidate). They stated that this lower improvement was probably the result of the double-blind controlled nature of their study and con-cluded that their findings reinforce the importance of conducting placebo-controlled trials to assess symptomatic outcomes.
In studies where, for whatever reason, use of a control group is not possible, there are two alternatives:
• The use of multiple baseline assessments, as practice effects are most likely to occur between the first and second testing sessions; • The use of parallel neuropsychological tests (tests with alternate
forms) [61] that are alternately administered to the diverse groups.
In studies in which several groups are being compared, it is of course highly desirable to assign patients by means of randomiza-tion. In our RCT, we employed a ‘pseudorandomized’ method called ‘minimization’. For relatively small trials, this method has proven to provide more balanced groups when compared with both restricted (stratified) and unrestricted (simple) randomization, and is able to incorporate more prognostic factors [64]. Disadvantages
of the method are that assignment can be predictable, that sta-tistical testing assumptions of randomized allocation may be compromised due to the ‘pseudorandom’ allocation adopted, and that it is organizationally more complex [64,65]. However, these
disadvantages are also true of other allocation methods such as stratification and, for some, adjustments can be made [64]. Other
authors suggest that minimization may be the platinum standard if randomization is the gold standard [66]. Free software for
carry-ing out minimization is available on the internet. Researchers are referred to the website of John Martin Bland, Professor of Health Statistics, with an overview of links to randomization (including minimization) software and services [215].
Problems with patient accrual and attrition over time have been reported in many trials. In some cases, this may be due to logisti-cal barriers, such as inconvenient timing of neuropsychologilogisti-cal testing, or the patient having to travel to a hospital to undergo cognitive rehabilitation and/or to be tested. Most interventions were carried out in patients with a history of treatment, in par-ticular of radiation therapy. One might argue that the cognitive deficits (whether caused by the tumor itself or by treatment) are most prevalent and severe at this stage of the illness trajectory, when treatment has been completed. Intervention at an earlier stage may be problematic. For example, Locke and colleagues indicated that problems with recruitment into a study of cognitive rehabilitation in patients with newly diagnosed brain tumors was largely due to the fact that patients were relatively early in their disease and treatment trajectory, and thus measurable cognitive impairment was limited [56].
the assessments played an important role in this high, sustained rate of participation. At the same time, facilitating training and assessment at home requires a larger travel budget, places greater demands on personnel, and requires flexibility on the part of both the researchers and the patients and their families to create optimal circumstances for carrying out training and assessments. Alternatively, with respect to cognitive rehabilitation, internet-based programs may also overcome these impediments. We are aware of only one completed study on internet-based cognitive rehabilitation [67], which was conducted in patients with memory
impairments after severe traumatic brain injury. In this study, although there were no significant differences observed between the active and control conditions on the primary outcome mea-sures (patient- and family-rated mood and memory), the authors suggest that the internet may still be a useful means of delivering compensatory cognitive rehabilitation [67]. They also report that
patients were highly satisfied with the treatment [68].
Many studies have been conducted on internet-based cognitive behavioral therapy. Although this type of therapy has a different purpose and targets a different patient population, the successes observed in these studies suggest that internet-based cognitive rehabilitation should be considered as a serious option for future research [69]. We are currently investigating the possibilities of
adapting both the retraining and strategy components of our cognitive rehabilitation program to an internet-based platform.
With regard to data ana lysis, the employment of multivariate techniques can be important in longitudinal studies with repeated measures and a battery of outcome measures. By means of these approaches the specific effects for the different groups over time can be tested. They may in part account for multiple statistical testing and thereby minimize the risk of type I errors.
Furthermore, although results at the group level (e.g., statisti-cal comparisons of group means) are very informative in studies of treatment effectiveness, they may also mask the variability in individual responses to interventions [70].
Defining responsiveness to an intervention or change over time at the individual patient level, that is, defining criteria on which to dichotomize change into ‘success’ or ‘failure’ of a treatment, is, however, complicated by the fact that the reliability of (neuro) psychological measures can be compromised by such factors as practice effects and regression to the mean. To prevent arbitrari-ness of the responsivearbitrari-ness criteria, more sophisticated methods than, for example, percentages of change have been proposed. In recent years, the Reliable Change Index has been introduced [71].
It represents a stringent measure of improvement at the indi-vidual level in the context of observed changes over time in a control group [72], and reflects the individual change beyond that
which can be attributed to measurement error and practice effects. Other measures with terms such as clinical significance, clinically meaningful change and minimum clinically important difference (e.g., see [72–74]) have also been introduced.
Additional analyses may help to identify the specific patient characteristics that predict positive individual response to a phar-macological or neuropsychological intervention. The knowledge gained can be used to inform future patients about the likelihood
that they will benefit (or not) from that intervention, and that it is worth the investment in time and effort. Conversely, if we can identify patients who are less likely to benefit from the inter-vention under study, we can advise them accordingly. Perhaps more importantly, and in particular for cognitive rehabilitation programs, we can use the knowledge to adapt our interventions to yield optimal benefit for a larger percentage of the target pop-ulation. We are currently conducting analyses on the possible sociodemographic, clinical, subjective cognitive symptom and neuropsychological baseline predictors of individual improvement based on a modification of the original Reliable Change Index in the participants of the cognitive rehabilitation program.
Another issue that is commonly encountered in many stud-ies of cognitive functioning in chronically ill patients is the discrepancy observed between the subjective (self-report) and objective (neuropsychological testing) measures of cognitive functioning [75–81]. The results of our trial suggest that this
dis-connect between subjective experience and test-based indica-tors of cognitive functioning not only applies in cross-sectional assessments, but also in assessing change in cognitive function-ing over time. The moderate ecological validity of neuropsycho-logical tests [82] and test situations may not entirely explain this
discrepancy (e.g., [80]). For example, in patients with multiple
sclerosis, it was found that patients’ performance on a battery of cognitive tests did, in fact, correlate with spouses’ and caregiv-ers’ perceptions of patients’ daily cognitive functioning [83]. In
another study in the same population, Middleton suggested that correlations between perceptions of daily cognitive function-ing and objective scores are higher for healthy controls than for patients [80]. Thus, the cause of the discrepancy may be found in
the perceptions of patients themselves. In fact, it has been gen-erally observed that self-reported cognitive functioning tends to correlate more highly with self-reported measures of emotional distress and well-being than with objective neuropsychological test performance [75,76,78,80,81].
A related issue concerns the common failure to include the presence of cognitive deficits as an inclusion criterion for stud-ies designed to test the efficacy of cognitive rehabilitation. In order to be able to measure an effect of an intervention, whether pharmaco logical or neuropsychological, patients need to exhibit some minimal level of cognitive impairment. Furthermore, the awareness that we must not rely on the Mini-Mental State Examination [84] as the only measure of cognitive functioning
has grown in recent years. As this measure has an unacceptably low sensitivity [85], we would again advise not to use it as the only
screening and/or evaluation measure.
cognitive deficits in patients undergoing anticancer therapy may, at least in part, be due to the fact that the patients are not yet experiencing cognitive symptoms, and thus may not be moti-vated to participate in a cognitive intervention or to adhere to the program once enrolled.
With respect to the assessment of outcome in cognitive inter-vention studies, we would point out that, although improvements in neuropsychological test performance and subjective cogni-tive symptoms are desirable results, improvement at the level of functional abilities may be the ultimate goal. For the purpose of evaluating functional outcome in individuals with cognitive deficits, questionnaires on instrumental activities of daily living, including tasks such as housekeeping, shopping and managing finances, are often used. The problem with most of these ques-tionnaires is that the activities that they measure may not be sensitive enough to detect changes (improvement) in the relatively mild-to-moderate cognitive deficits experienced by patients with brain tumors who are candidates for cognitive rehabilitation. In our own research, as an alternative to measures of instrumental activities of daily living, we employed the Community Integration Questionnaire, which assesses productive activity, independent living and social activity [86]. We also used a measure of fatigue,
and found some evidence that mental fatigue improves following cognitive rehabilitation.
It should also be noted that maintaining rather than improv-ing neuropsychological functionimprov-ing may be a legitimate goal of a cognitive intervention in patients with brain tumors. This may particularly be the case when cognitive decline is expected (e.g., with measurements over a longer interval, in which practice effects may be diminished).
A recommendation that is based on both our experience and that of others, is that studies of cognitive rehabilitation programs should take into account the possibility of a ‘delayed’ intervention effect on cognitive test performance. We observed this in our RCT, and it has also been reported in earlier studies of cogni-tive rehabilitation in other patient populations [87–90]. It has been
suggested that patients may require a longer period of time to integrate learned strategies into their daily routine.
Finally, future cognitive rehabilitation studies in patients with brain tumors will face the problem, common for all behavioral treatment studies, that it is not feasible to incorporate a ‘placebo’ condition in which patients are required to attend a series of ses-sions (comparable to the intervention group) in which no truly substantive rehabilitation program is offered. As a consequence, it will be difficult to exclude the possibility that the positive results of the cognitive rehabilitation are not only attributable to the cog-nitive treatment itself, but also to other nonspecific factors such as attention [91,92]. At the same time, careful ana lysis of trial data can
provide some insight into the probability of a placebo effect. For example, in our study, we could not exclude the possibility that the immediate decline in subjective cognitive symptoms could be due to nonspecific treatment effects. However, nonspecific treatment effects as the sole or even primary explanation for the improvements in objective test performance was less likely, con-sidering the initially equal improvement in neuropsychological
performance for both groups, and the intervention effect after a 6-month interval, in which possible placebo effects may be assumed to be absent. Moreover, it has been suggested that non-specific treatment effects, such as social support and a credible treatment rationale, form an integral part of the treatment, and that results from trials without placebo are more generalizable to clinical practice [93].
Five-year view
In recent years, the interest in interventions for tumor- or treat-ment-related cognitive deficits in patients with brain tumors has clearly grown, resulting in an expansion of novel studies of this subject. Identification of studies on Clinicaltrials.gov shows that important data will become available in the next few years. It is therefore expected that insight in this topic will grow considerably.
First, the identification of more targeted brain tumor treatments is anticipated. Results from the study on gliadel wafers [203] are
forthcoming and a trial on avoidance of the hippocampus during WBRT in patients with brain metastases is opening soon [49].
With regard to prevention studies in patients with brain tumors, the results of a RCT on the possible preventive effects of meman-tine [205] will become available in the next few years. Studies of
pharmacological treatment of cognitive deficits that have been conducted in patients with cancers outside the CNS [77,94–96]
suggest that it might be worthwhile to determine the preventive effects of erythropoietin or similar stimulating agents in these patients and in those with brain cancer.
The number of successful studies of pharmacological agents for the treatment of existing cognitive deficits in patients with brain tumors is still very low. In the coming years, the results of RCTs on donepezil [210] and armodafinil [212] in patients with
brain tumors are anticipated. Indeed, modafinil has been found to be effective in recent studies in patients with cancers outside the CNS [97–99] who have cognitive deficits, which suggests that
the cognitive effects of this agent should be investigated more thoroughly in these populations.
Cognitive rehabilitation programs in patients with brain tumors have only recently been the subject of study [48,56,57]. Results show
that they are feasible and that they yield positive effects, even in the long term. Replication of studies that have provided positive results and further refinement of available programs is, however, still needed.
convenient and flexible alternative to in-clinic programs, although their efficacy needs to be tested. Other approaches to improving cognitive functioning in patients with a brain tumor should also be considered. For example, it has been suggested that (offline repetitive) transcranial magnetic stimulation might be useful in the rehabilitation of cognitive functions [100,101], although
evidence of long-term effects is needed [101].
Recent findings also suggest that physical exercise may be effective in delaying or ameliorating cognitive decline in older adults with and without cognitive decline [102–104]. The evidence
stems from epidemiologic [105,106], experimental [107],
neuro-anatomical [108] and animal studies [107,109]. Furthermore, the
benefits of physical activity on fatigue, depression, fitness and happiness have frequently been demonstrated in patients with diverse cancer types (other than brain cancer) [110–112]. The effects
of physical exercise on cognitive functioning in patients with a brain tumor have yet to be investigated. Our group is preparing a study of the feasibility and effectiveness of physical exercise in predominantly low-grade glioma patients in improving cognitive functioning, fatigue, mood and QoL.
Future research on cognitive interventions should continue to be based on a clear (albeit sometimes preliminary) rationale, employ randomized or well-matched controlled designs and a
comprehensive neuropsychological test battery, and analyze data with multivariate statistics at the group level and preferably indi-vidual measures of improvement. In order to avoid or minimize problems with enrollment and adherence, and to yield opti-mal treatment effects, future studies should consider screening patients for the presence of both subjective and objective cognitive problems, and take logistical considerations concerning planning and location of assessments (and, if applicable, training sessions) into account.
In this way, clear insights into the treatment of cognitive defi-cits in patients with a brain tumor will be obtained and become applicable in clinical practice.
Acknowledgements
The authors would like to thank Wobbe P Zijlstra for his statistical advice.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Cognitive deficits resulting from a brain tumor or its treatment can substantially impact on patients’ lives.
• Until recently, relatively few studies investigated prevention or treatment of cognitive deficits in patients with brain tumors.
• The interest in interventions for tumor- or treatment-related cognitive deficits in brain tumors has clearly grown, and data of promising novel studies are anticipated.
• Although methodologies have also become stronger, many studies have methodological limitations, of which the most important is the failure to employ an appropriate control group in order to rule out practice effects.
• The effects of erythropoietin and similar agents in the pharmacological prevention of cognitive deficits need to be determined. • Potentially successful pharmacological treatments for cognitive deficits may be modafinil and similar agents.
• However, pharmacological prevention and treatment studies suffer from problems with patient enrollment and attrition.
• Research experience and results suggest that cognitive rehabilitation is a very promising method of treating cognitive deficits. However, studies should be replicated and cognitive rehabilitation programs should be further refined.
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